The survival rate for patients with metastatic colon cancer is a dismal 11%, which translates to over 45,000 lives lost annually. This is in spite of improved screening and the availability of several new targeted therapies. Agents such as bevacizimab or cetuximab lead to improvements in survival times of only 6 months or less. Additionally, some are contra-indicated in patients whose tumors have specific mutations (K-Ras, for example). Therefore, new therapeutic approaches are urgently needed. This proposal focuses on the role of a cytokine receptor constituent known as IL4Ralpha, specifically when it is expressed on epithelial tumor cells. IL4Ralpha has been well-studied in lymphocytes where it is known to mediate signals responsible for production of certain immunoglobulins, for example. The major role of the IL4Ralpha pathway in immunity relates to allergic reactions and it is a validated drug target in atopic conditions such as asthma. While IL4Ralpha appears widely expressed in colon tumor cells, its function there is largely unknown. We hypothesize that signaling through IL4Ralpha on colon cancer cells, activated by either IL4 or IL13, promotes colon tumor progression and metastasis. We will test this hypothesis by answering three main questions: (1) How does colonic tumor cell IL4Ralpha respond to host-produced IL4 or IL13 either at the primary or metastatic site;(2) What specific processes are regulated by IL4Ralpha in epithelial cells, and are the signaling pathways different depending on whether the ligand is IL4 or IL13;and (3) How does epithelial IL4Ralpha impact de novo tumorigenesis? At the conclusion of these studies, we will have determined whether IL4Ralpha is a useful target for metastatic colon cancer. Since drugs that impact IL4Ralpha signaling are already developed for allergic and atopic diseases, there is potential for rapid translation to the cancer clinic. Ultimately, this will lead to better therapy options for patients with metastatic colon cancer. PUBLIC HEALTH RELEVANCE: Colon cancer is the third leading cause of cancer-related deaths in men and women in the US, with only an 11% survival rate for patients with metastatic disease. Interleukin-4 and interleukin-13 are related proteins that bind to the IL4 receptor and perhaps contribute to colon cancer. Our goal is to define the roles of these proteins in colon cancer progression and metastasis, to test if their inhibition would be a realistic therapy.